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Objective:To observe the effects of sacubitril/valsartan (LCZ696) on viral replication and cardiomyocyte apoptosis in mice with coxsackievirus B3 (CVB3)-induced viral myocarditis (VMC) and to analyze the underlying mechanisms.Methods:Forty BALB/c mice were randomly divided into four groups with 10 in each group: Sham, Sham+ LCZ696, VMC, and VMC+ LCZ696 groups. VMC model was established by intraperitoneal injection of 0.1 ml of CVB3 with a concentration of 10 6 TCID 50/ml into BALB/c mice, while the sham intervention was an equal volume of saline. The day of virus injection was defined as day 0. LCZ696 was administered by gavage at a dose of 60 mg/kg every day for seven consecutive days starting from day 1. Mouse survival rates were calculated. Echocardiography was used to evaluate the cardiac function of mice. The level of creatine kinase-MB (CK-MB) was detected by ELISA. Western blot was used to detect the levels of inflammatory cytokines (IL-6, TNF-α), apoptosis-related proteins (caspase-3, cleaved-caspase-3, Bax, Bcl-2), CVB3 surface protein (VP-1) and p-AKT/AKT in the hearts of mice. CVB3 mRNA in mouse hearts was measured by PCR. Inflammatory cell infiltration and cell apoptosis in mouse hearts were observed by HE staining and TUNEL staining, respectively. Results:Compared with the Sham group, the mice in the VMC group had a decreased survival rate and impaired cardiac function ( P<0.05). The levels of CK-MB, IL-6, TNF-α, cleaved-caspase-3/caspase-3, Bax/Bcl-2, VP-1, and CVB3 mRNA in the hearts of VMC mice increased significantly ( P<0.05), accompanied by increased expression of AKT, decreased phosphorylation of AKT ( P<0.05) and increased cell apoptosis. LCZ696 reversed the above changes. It could increase the survival rate, improve the cardiac function ( P<0.05), decrease cardiac inflammation, cell apoptosis and viral replication ( P<0.05), and increase the phosphorylation of AKT ( P<0.05). LCZ696 had no significant effects on the survival rate, cardiac function, myocardial injury, cardiac inflammation, cell apoptosis, viral replication or the expression of PI3K/AKT signaling pathway-related proteins in normal mice. Conclusions:LCZ696 could significantly inhibit cardiomyocyte apoptosis and reduce CVB3 replication in the hearts of VMC mice by regulating the PI3K/AKT pathway, thereby improving mouse cardiac function and survival rate.
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Objective:To detect whether Toll-like receptor 4 ( TLR4) polymorphisms contributed to primary open angle glaucoma (POAG) in a Chinese population. Methods:A Chinese cohort, including 799 unrelated POAG patients and 799 unrelated controls, was enrolled in our case-control association study. The data was collected at Sichuan Provincial People's Hospital from May 2014 to March 2018. TLR4 functional single nucleotide polymorphisms (SNPs), including rs4986790 and rs4986791, were genotyped by SNaPshot method. Genotype and allele frequencies of the two SNPs were evaluated. This study was approved by the Institutional Review Boards of the Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (No.2016-58), and complied with the guidelines of the Declaration of Helsinki. Written informed consents were obtained from all subjects prior to the study. Results:Allelic association analysis revealed that there were no significant association detected in the allelic distributions between the POAG cases and controls for SNPs rs4986790 ( P=0.317) and rs4986791 ( OR=1.000, 95% CI =0.062 5-16.002 2, P=1.000) in the TLR4 gene. Conditional analysis of the two SNPs did not show any significant difference in genotype and allele frequency between the case and the control groups. No association of the two SNPs with POAG was detected under four different genetic models, including homozygote, heterozygote, dominant and recessive models. Conclusions:Polymorphisms rs4986790 and rs4986791 in the TLR4 gene are not related to POAG in the Chinese cohort.
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<p><b>OBJECTIVE</b>To observe the impact of the JNK inhibitor XG-102 in a diet-induced rat model of non-alcoholic steatohepatitis.</p><p><b>METHODS</b>Forty-eight Sprague-Dawley male rats were subjected to a percutaneous superior mesenteric vein retention catheter operation and fed with a standard diet for 10 days, after which the rats were randomly divided into the following three groups: normal control (NC) group; high-fat (HF) model group; XG-102 treatment group. The HF group was fed an HF diet and treated with 0.9% sodium chloride for 16 weeks. The XG-102 group was fed an HF diet for 16 weeks and simultaneously treated with XG-102 (1 mg/kg) once per day for 4 weeks. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), homeostasis model of assessment insulin resistance (HOMA-IR) and tumor necrosis factor-alpha (TNFa) were measured. Liver histological changes were observed. The protein expressions of phospho-c-Jun and cleaved caspase-3 were detected by western blotting.</p><p><b>RESULTS</b>Compared with the NC group, the HF group showed significantly higher levels of serum ALT, AST, TC, TG, HOMA-IR and TNFa (P<0.05). Compared with the HF group, the XG-102 group showed significantly lower levels of serum ALT, AST, TC, TG, HOMA-IR and TNFa (P<0.05). The HF group also showed significantly higher protein expression of phospho-c-Jun and cleaved caspase-3 than the NC group (P<0.05) and the XG-102 group (P<0.05).</p><p><b>CONCLUSION</b>The JNK inhibitor XG-102 may ameliorate lipid metabolism, reduce insulin resistance, decrease liver injury and inhibit hepatocytes apoptosis.</p>